This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. According to the latest NHANES survey (1999-2002), 29% of women at childbearing age (20-39 years old) are obese. At the same time, autoimmune diseases including Type I diabetes are also increasing, indicating a likely link between maternal obesity (MO) and altered immune system development. Major components of immune system development are accomplished during the fetal and neonatal stages. Our preliminary data show that MO led to systemic inflammation in fetuses and the expression of toll like receptor (TLR) 4 was elevated. We hypothesized that MO induces systemic inflammation in fetus, which promotes survival of thymocytes specific to host-derived antigens, increasing the incidence of autoimmune diseases including type I diabetes in offspring. We are using well-established non-obese diabetic (NOD) mice fed control (Con) or obesogenic (OB) diet to study the effect of MO on the incidences of offspring type I diabetes. We also utilize TLR4 knockout mice to study the role of TLR4 in the fetal immune system development. Based on the data obtained from this study, the PI will further explore mechanisms associated with the fetal immune system development and immune tolerance, and develop specific strategies to cope with autoimmune diseases. Knowledge obtained in this study will provide targets for interventions to ensure the proper development of the immune system, improving the quality of life for the offspring of the increasing number of obese pregnant women in this country.